US7655663B2 - Fluoropyrrolidines having dipeptidyl peptidase enzyme inhibitory activity - Google Patents

Fluoropyrrolidines having dipeptidyl peptidase enzyme inhibitory activity Download PDF

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US7655663B2
US7655663B2 US12/042,595 US4259508A US7655663B2 US 7655663 B2 US7655663 B2 US 7655663B2 US 4259508 A US4259508 A US 4259508A US 7655663 B2 US7655663 B2 US 7655663B2
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Peter Aranyi
Laszlo Balazs
Imre Bata
Sandor Batori
Eva Boronkay
Philippe Bovy
Karoly Kanai
Zoltan Kapui
Edit Susan
Tibor Szabo
Lajos T. Nagy
Katalin Urban-Szabo
Marton Varga
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Sanofi Aventis France
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Definitions

  • the present invention relates to the novel compound of the general formula (I) possessing dipeptidyl-peptidase-IV enzyme inhibitory activity, as well as their salts, solvates and isomers, to the therapeutic application of the compounds of the general formula (I), to the pharmaceutical compositions containing the compounds of the general formula (I), to the process for their preparation and to the new intermediates of the general formulae (II), (III), (V), (VII), (VIII) and (IX).
  • the enzyme dipeptidyl-peptidase-IV (DPP-IV), which is identical with the lymphocyte surface glycoprotein CD26, a polypeptide with the molar mass of 110 k Dalton, is formed in the tissues and organs of mammals. This enzyme can be found, among others, in the liver, in the Langerhans islets, in the renal cortex, in the lungs, and in certain tissues of the prostate and small intestine. Significant DPP-IV activity can be observed furthermore in the body fluids (as for instance in the plasma, serum and urine).
  • DPP-IV is a serine protease type enzyme, which has the unique specificity to cleave dipeptides from the N-terminals of peptides where the penultimate amino acid is primarily proline, alanine or hydroxy proline.
  • DPP-IV enzyme is responsible for the decomposition of the glucagon-like peptides, peptide-1 (GLP-1) and peptide-2 (GLP-2) in the body.
  • the enzyme GLP-1 strongly stimulates the insulin production of the pancreas, thus it has a direct, favourable effect on the glucose homeostasis, therefore DPP-IV inhibitors are suitable for the treatment and prevention of non-insulin dependent diabetes mellitus (NIDDM) and other diseases related with the DPP-IV enzyme activity including but not limited to diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, poriasis, intestinal distress, constipation, autoimmune disorders such as enchephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodystrophy, and tissue damage, psychosomatic, depressive, and neurophsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allergies, inflammation, arthritis, transplant rejection,
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, hal
  • R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups,
  • R1, B or R2 and R3 are those groups which are listed in Tables 1 to 3 including any combinations thereof, for example (2S)-4,4-difluoro-1-(2- ⁇ [8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl]exo-amino ⁇ acetyl)-2-pyrrolidine carbonitrile; (2S,4S)-4-fluoro-1-(2- ⁇ [8-(2-pyrazinyl)-8-azabicyclo-[3.2.1]-oct-3-yl]exo-amino ⁇ acetyl)-2-pyrrolidinecarbonitrile; (2S)-4,4-Difluoro-1-(2- ⁇ [1-(2-pyrazinyl)piperidin-4-yl]amino ⁇ acetyl)-2-pyrrolidine carbonitrile; (2S)-4,4-Difluoro-1-(2- ⁇ [1-(5-cyano
  • Term “nitrogen containing aromatic moiety consisting of one or two aromatic rings” includes all such ring systems known at the priority date of our present patent application.
  • halogen atom means fluorine, chlorine, bromine, or iodine atom.
  • C1-4 alkyl group and “C1-4 alkoxy group” mean linear or branched chain aliphatic hydrocarbon groups containing 1-4 carbon atoms.
  • the compounds of the general formula (I) according to our invention can be prepared by the alkylation of the primary amines of the general formula (II)— wherein the meanings of R 1 and B are the same as given above—with the chloroacetyl derivative of the general formula (III)—wherein the meanings of R 2 and R 3 are as given above- and, if desired, by transforming the resulting compounds into one of their salts or solvates (Scheme 1).
  • the chloroacetyl derivatives of the general formula (III) are applied in excess, and the resulting hydrogen chloride is bound by various acid binding agents, preferably by a base, such as for instance triethylamine, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-terc-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine—bound to a resin (PBEMP)—, which is known as super base.
  • a base such as for instance triethylamine, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-terc-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine—bound to a resin (PBEMP)—, which is known as super base.
  • DBU 1,8-diazabicy
  • the primary amines of the general formula (II) are prepared in a two-step synthesis (Scheme 2).
  • the arylation reaction can be carried out in polar, protic or aprotic solvents, between 25 and 150° C., preferably in alcohols (ethanol, n-butanol, n-pentanol), or without solvent in microwave oven, using an acid binder, for instance the excess of the amine, or DBU.
  • polar, protic or aprotic solvents between 25 and 150° C., preferably in alcohols (ethanol, n-butanol, n-pentanol), or without solvent in microwave oven, using an acid binder, for instance the excess of the amine, or DBU.
  • the protecting group Y is removed from the arylated amine of the general formula (V)—wherein the meanings of R 1 and B are the same as defined above—by acidic hydrolysis.
  • the reaction is carried out in aqueous hydrochloric acid or in ethanolic hydrogen chloride solution at a temperature between 25 and 78° C. to yield the aliphatic or cyclic primary amines of the general formula (II)—wherein the meanings of R 1 and B are the same as defined above.
  • R 1 stands for an acyl group of formula R 1a —CO
  • the protecting group Y is cleaved under acidic conditions, preferably by use of trifluoroacetic acid in dichloromethane solution, at 0-30° C., to obtain the amines of the general formula (II), wherein the meaning of R 1 is the group of formula R 1a —CO.
  • the starting compounds are the fluoroproline derivatives, preferably L-fluoroproline derivatives—wherein the meanings of R 2 and R 3 are the same as defined above—with a nitrogen protected with tert-butoxycarbonyl group.
  • fluoroproline derivatives preferably L-fluoroproline derivatives—wherein the meanings of R 2 and R 3 are the same as defined above—with a nitrogen protected with tert-butoxycarbonyl group.
  • These compounds can be prepared by methods written in the literature (Tetrahedron Lett. 1998, 39, 1169).
  • a mixed anhydride is prepared with pivaloyl chloride or chloroformic acid ethyl ester, then the carbamoyl derivatives of the general formula (VII)—wherein the meanings of R 2 and R 3 are the same as defined above—are formed.
  • the reaction is preferably carried out in a halogenated solvent (CHCl 3 , CH 2 Cl 2 ), at 0-25° C.
  • a halogenated solvent CHCl 3 , CH 2 Cl 2
  • the tert-butoxycarbonyl group is cleaved in ethanolic hydrogen chloride solution.
  • the hydrolysis takes place at 0-25° C. and the hydrochlorides of the carboxamides of the general formula (VIII)—wherein the meanings of R 2 and R 3 are the same as defined above—are obtained.
  • the fluoropyrrolidinecarboxamides of the general formula (VIII) thus obtained are in the third step acylated with chloroacetyl chloride, preferably at 0° C., in a halogenated solvent (CHCl 3 , CH 2 Cl 2 ).
  • a halogenated solvent CHCl 3 , CH 2 Cl 2
  • the chloroacetylcarbamoyl derivatives of the general formula (IX) are dehydrated to yield the chloroacetylcyano derivatives of the general formula (III)—wherein the meanings of R 2 and R 3 are the same as defined above. Dehydration is preferably carried out with phosphorous oxychloride in dichloromethane at the boiling point of the reaction mixture.
  • DPP-IV enzyme inhibitory activities of the compounds with the general formula (I) were determined by the following method:
  • Standard curve of AMC is linear up to 31.25 ⁇ M concentration, that is why we used the relative fluorescence unit (RFU) of the AMC formed. It is detected by using 360 nm excitation and 465 emission filters (30 ⁇ s integration time, Gain 25, No. of Flashes 50) by Tecan Spectrofluor Plus plate reader. Under these conditions enzyme reaction is linear for at least 30 min, and the enzyme dependence is linear up to 2.5 ⁇ g protein (up to 700 RFU).
  • the assay is designed to detect the active inhibitors as efficiently as possible, using a 60 min preincubation time at 37° C.
  • the fluorescence (RFU) of AMC formed is detected using 360 nm excitation and 465 emission filters in Tecan spectrofluor Plus plate reader (30 ⁇ s integration time, Gain 25 No. of Flashes 50). Inhibition % are calculated using the RFU of control and RFU of blank.
  • IC 50 values characteristic for the enzyme inhibitory effect of the compounds of the general formula (I) according to the invention are smaller than 100 nM.
  • the compounds of the general formula (I) and their salts solvates and isomers can be formulated to orally or parenterally applicable pharmaceutical compositions by methods known per se, by mixing them with one or more pharmaceutically accepted excipients and can be administered as a unitary dosage form.
  • the appropriate unitary dosage form comprise the oral forms, such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, the sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-cutaneous, intramuscular or intra-venous forms, the rectal forms and the implants.
  • the compounds of the invention may be used as creams, gels, ointments of lotions.
  • a unitary dosage form for a compound according to the invention in the form of a tablet, can comprise the following ingredients:
  • a compound of the general formula (I) 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Maize starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg
  • Daily dose of the compounds of the general formula (I) may depend on several factors, thus the nature and seriousness of the disease of the patient, the mode of application and on the compound itself.
  • FIG. 1 shows compounds of the general formula (I),
  • FIG. 2 shows compounds of the general formula (II),
  • FIG. 3 shows compounds of the general formula (III),
  • FIG. 4 shows compounds of the general formula (IV),
  • FIG. 5 shows compounds of the general formula (V),
  • FIG. 6 shows compounds of the general formula (VI),
  • FIG. 7 shows compounds of the general formula (VII),
  • FIG. 8 shows compounds of the general formula (VIII),
  • FIG. 9 shows compounds of the general formula (IX),
  • FIG. 10 shows compounds of the general formula (X),
  • FIG. 11 shows formula (1)
  • FIG. 12 shows formula (2)
  • FIG. 13 shows formula (3)
  • FIG. 14 shows formula (4)
  • FIG. 15 shows formula (5)
  • FIG. 16 shows formula (6)
  • FIG. 17 shows formula (7).
  • R 1 is 2-pyrimidinyl group
  • B means a group of formula (4)
  • R 2 and R 3 mean fluorine atom in general formula (I).
  • R 1 means 2-pyrazinyl-group
  • B means a group of formula (4)
  • R 2 means hydrogen atom
  • R 3 means fluorine atom.
  • R 2 means hydrogen atom and R 3 means fluorine atom.
  • R 2 means hydrogen atom and R 3 means fluorine atom.
  • R 3 means fluorine atom.
  • 2.54 g (15 mmol) of (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride are suspended in 60 ml of dichloromethane and 4.6 ml (33 mmol) of triethylamine are added thereto.
  • 1.27 ml (16 mmol) of chloroacetyl chloride dissolved in 15 ml of dichloromethane are added dropwise below ⁇ 10° C.
  • reaction mixture is stirred for an hour and the suspension is poured into 500 ml of ethylacetate, the precipitated triethylamine hydrochloride is filtered off, the filtrate is concentrated and purified by chromatography using a chloroform-methanol 4:1 mixture.
  • R 2 means hydrogen atom and R 3 means fluorine atom.
  • R 1 is 2-pyrazinyl group
  • B means a group of formula (I)
  • R 2 and R 3 mean fluorine atom in general formula (I).
  • R 1 is 5-cyano-pyridin-2-yl group
  • B means a group of formula (I)
  • R 2 and R 3 mean fluorine atom in general formula (I).
  • F F 162-163° C., dihydrochloride, white crystals 55 (1)

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Abstract

The present invention relates to new, potent DPP-IV enzyme inhibitors of the general formula (I), which contain fluorine atoms.

Description

The present invention relates to the novel compound of the general formula (I) possessing dipeptidyl-peptidase-IV enzyme inhibitory activity, as well as their salts, solvates and isomers, to the therapeutic application of the compounds of the general formula (I), to the pharmaceutical compositions containing the compounds of the general formula (I), to the process for their preparation and to the new intermediates of the general formulae (II), (III), (V), (VII), (VIII) and (IX).
The enzyme dipeptidyl-peptidase-IV (DPP-IV), which is identical with the lymphocyte surface glycoprotein CD26, a polypeptide with the molar mass of 110 k Dalton, is formed in the tissues and organs of mammals. This enzyme can be found, among others, in the liver, in the Langerhans islets, in the renal cortex, in the lungs, and in certain tissues of the prostate and small intestine. Significant DPP-IV activity can be observed furthermore in the body fluids (as for instance in the plasma, serum and urine).
DPP-IV is a serine protease type enzyme, which has the unique specificity to cleave dipeptides from the N-terminals of peptides where the penultimate amino acid is primarily proline, alanine or hydroxy proline.
DPP-IV enzyme is responsible for the decomposition of the glucagon-like peptides, peptide-1 (GLP-1) and peptide-2 (GLP-2) in the body. The enzyme GLP-1 strongly stimulates the insulin production of the pancreas, thus it has a direct, favourable effect on the glucose homeostasis, therefore DPP-IV inhibitors are suitable for the treatment and prevention of non-insulin dependent diabetes mellitus (NIDDM) and other diseases related with the DPP-IV enzyme activity including but not limited to diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, poriasis, intestinal distress, constipation, autoimmune disorders such as enchephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodystrophy, and tissue damage, psychosomatic, depressive, and neurophsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allergies, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart failure, tumors, and stress-induced abortions.
Our aim was to prepare new, effective, stable and safe DPP-IV inhibitors.
We have found that the compounds of the general formula (I) wherein R1 stands for:
    • a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, tetrazolyl or triazinyl rings; which are, optionally, mono- or disubstituted independently from each other by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group, amino group or phenyl group; or
    • thienyl or furyl or benzyl group; or
    • p-toluenesulfonyl group; or
    • the acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more C1-4 alkyl- and/or C1-4 alkoxy- or nitro-group or halogen atom; phenylethenyl group, or a phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methyl-piperazin-1-yl, or pyrrolidin-1-yl group;
  • B stands for a group according to the formula (1) or (2) or (3) or (4) or (5) or (6) or (7);
  • R2 stands for hydrogen atom or fluoro atom;
  • R3 stands for fluoro atom—
  • as well as the salts, isomers and solvates of these compounds have significant advantages as regards their activity, duration of action, stability and toxicity in comparison with the state of the art.
In agreement with the accepted terminology, the configuration of carbon atom in position 2 of the fluoropyrrolidine group is favourably S, whereas that of carbon atom in position 4 is S or R.
One embodiment of the present invention includes compounds of the general formula (I)—wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
    • thienyl or furyl group; or
    • p-toluenesulfonyl group; or
    • acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
      B stands for
    • a group of formula (1) or (2) or (3) or (4) or (5) or (6) or (7);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers solvates and hydrates thereof.
Another embodiment of the present invention includes compounds of the general formula (I)—wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
  • a thienyl or furyl group; or
  • a p-toluenesulfonyl group; or
  • an acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group;
    phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
    B stands for
    • a group of formula (I);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers solvates and hydrates thereof.
Another embodiment of the present invention includes compounds of the general formula (I)—wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
  • a thienyl or furyl group; or
  • a p-toluenesulfonyl group; or
  • an acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
    B stands for
    • a group of formula (2);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers solvates and hydrates thereof.
Another embodiment of the present invention includes compounds of the general formula (I)—wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
  • a thienyl or furyl group; or
  • a p-toluenesulfonyl group; or
  • an acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
    B stands for
    • a group of formula (3);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers solvates and hydrates thereof.
Another embodiment of the present invention includes compounds of the general formula (I)—wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
  • a thienyl or furyl group; or
  • a p-toluenesulfonyl group; or
  • an acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
    B stands for
    • a group of formula (4) or (5);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers solvates and hydrates thereof.
Another embodiment of the present invention includes compounds of the general formula (I) —wherein R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
  • a thienyl or furyl group; or
  • a p-toluenesulfonyl group; or
  • an acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
    B stands for
    • a group of formula (6) or (7);
  • R2 stands for hydrogen atom or fluorine atom;
  • R3 stands for fluorine atom—
  • and salts, isomers, tautomers, solvates and hydrates thereof.
Preferred compound of the general formula (I) are wherein R1, B or R2 and R3 are those groups which are listed in Tables 1 to 3 including any combinations thereof, for example (2S)-4,4-difluoro-1-(2-{[8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl]exo-amino}acetyl)-2-pyrrolidine carbonitrile; (2S,4S)-4-fluoro-1-(2-{[8-(2-pyrazinyl)-8-azabicyclo-[3.2.1]-oct-3-yl]exo-amino}acetyl)-2-pyrrolidinecarbonitrile; (2S)-4,4-Difluoro-1-(2-{[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile; (2S)-4,4-Difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile; (2S)-4,4-Difluoro-1-(2-{[1-(6-chloropyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile; (2S)-4,4-Difluoro-1-(2-{[1-(6-cyanopyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile;
Term “nitrogen containing aromatic moiety consisting of one or two aromatic rings” includes all such ring systems known at the priority date of our present patent application.
Term “halogen atom” means fluorine, chlorine, bromine, or iodine atom. “C1-4 alkyl group” and “C1-4 alkoxy group” mean linear or branched chain aliphatic hydrocarbon groups containing 1-4 carbon atoms.
The compounds of the general formula (I) according to our invention can be prepared by the alkylation of the primary amines of the general formula (II)— wherein the meanings of R1 and B are the same as given above—with the chloroacetyl derivative of the general formula (III)—wherein the meanings of R2 and R3 are as given above- and, if desired, by transforming the resulting compounds into one of their salts or solvates (Scheme 1).
In the course of the alkylation the chloroacetyl derivatives of the general formula (III) are applied in excess, and the resulting hydrogen chloride is bound by various acid binding agents, preferably by a base, such as for instance triethylamine, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-terc-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine—bound to a resin (PBEMP)—, which is known as super base. The reaction is preferably performed at a temperature between 25 and 70° C.
The primary amines of the general formula (II) are prepared in a two-step synthesis (Scheme 2). In the first step the starting cyclic secondary amine of the general formula (IV)—wherein the meaning of Y is hydrogen atom, acetyl, or tert-butoxycarbonyl group—are arylated, preferably with the aryl halogenides of the general formula (X), wherein the meaning of R1 is the same as given above and X stands for halogen atom. Depending on the meaning of R1 the arylation reaction can be carried out in polar, protic or aprotic solvents, between 25 and 150° C., preferably in alcohols (ethanol, n-butanol, n-pentanol), or without solvent in microwave oven, using an acid binder, for instance the excess of the amine, or DBU.
For starting material the free amines or protected secondary amines of the general formula (IV)—known from the literature—are used, thus 4-acetaminopiperidine (B=formula (I), Y =COCH3) (U.S. Pat. No. 3,225,037);
4-tert-butoxycarbonylaminopiperidine (B=formula (I), Y=COOC(CH3)3) (J. Med. Chem. 1999, 42, 2706); 3-(S)-tert-butoxycarbonylaminopiperidine (B=formula (2)) and 3-(S)-tert-butoxycarbonylaminopyrrolidine (B=formula (3)) (Synth. Comm. 1998, 28, 3919) in the last two cases Y=COOC(CH3)3; tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-exo-carbamate (B=formula (4), tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-endo-carbamate (B=formula (5)) (J. Med. Chem. 1991, 34, 656), tert-butyl 9-azabicyclo[3.3.1]-non-3-yl exo-carbamate (B=formula (6)) and tert-butyl 9-azabicyclo-[3.3.1]-non-3-yl-endo-carbamate (B=formula (7)), (J. Med. Chem. 1993, 36, 3720)) (Y=COOC(CH3)3).
In the second step the protecting group Y is removed from the arylated amine of the general formula (V)—wherein the meanings of R1 and B are the same as defined above—by acidic hydrolysis. The reaction is carried out in aqueous hydrochloric acid or in ethanolic hydrogen chloride solution at a temperature between 25 and 78° C. to yield the aliphatic or cyclic primary amines of the general formula (II)—wherein the meanings of R1 and B are the same as defined above.
If R1 stands for an acyl group of formula R1a—CO, the compounds of the general formula (IV)—wherein the meaning of Y is tert-butoxycarbonyl group—are reacted with the acid derivatives of the general formula R1a—COZ—wherein the meaning of Z is a leaving group, preferably a chloro atom—advantageously at a temperature around 0° C., by using an inorganic or organic base, preferably triethylamine as acid binding agent. From the compounds of the general formula (V) the protecting group Y is cleaved under acidic conditions, preferably by use of trifluoroacetic acid in dichloromethane solution, at 0-30° C., to obtain the amines of the general formula (II), wherein the meaning of R1 is the group of formula R1a—CO.
The 1-(2-chloroacetyl)-2-pyrrolidinecarbonitriles of the general formula (III)—wherein the meanings of R2 and R3 are the same as defined above—are prepared in a four-step synthesis (Scheme 3).
The starting compounds are the fluoroproline derivatives, preferably L-fluoroproline derivatives—wherein the meanings of R2 and R3 are the same as defined above—with a nitrogen protected with tert-butoxycarbonyl group. These compounds can be prepared by methods written in the literature (Tetrahedron Lett. 1998, 39, 1169). In the first step a mixed anhydride is prepared with pivaloyl chloride or chloroformic acid ethyl ester, then the carbamoyl derivatives of the general formula (VII)—wherein the meanings of R2 and R3 are the same as defined above—are formed.
The reaction is preferably carried out in a halogenated solvent (CHCl3, CH2Cl2), at 0-25° C.
In the second step the tert-butoxycarbonyl group is cleaved in ethanolic hydrogen chloride solution. The hydrolysis takes place at 0-25° C. and the hydrochlorides of the carboxamides of the general formula (VIII)—wherein the meanings of R2 and R3 are the same as defined above—are obtained.
The fluoropyrrolidinecarboxamides of the general formula (VIII) thus obtained are in the third step acylated with chloroacetyl chloride, preferably at 0° C., in a halogenated solvent (CHCl3, CH2Cl2). Thus the chloroacetylcarbamoyl derivatives of the general formula (IX)—wherein the meanings of R2 and R3 are the same as defined above—are formed. In the fourth step the chloroacetylcarbamoyl derivatives of the general formula (IX) are dehydrated to yield the chloroacetylcyano derivatives of the general formula (III)—wherein the meanings of R2 and R3 are the same as defined above. Dehydration is preferably carried out with phosphorous oxychloride in dichloromethane at the boiling point of the reaction mixture.
Figure US07655663-20100202-C00001
Figure US07655663-20100202-C00002
Figure US07655663-20100202-C00003
Biological Investigations
DPP-IV enzyme inhibitory activities of the compounds with the general formula (I) were determined by the following method:
Applied Conditions of the Assay:
  • DPP-IV. source: solubilized crude extractum from CaCo/Tc-7 cells
    • content: 0.8-1 μg/assay
  • Substrate: H-Gly-Pro-AMC (Bachem)
  • Reaction: 1 hour preincubation with samples at 37° C.,
    • 30 min reaction time at 37° C.,
  • Stop solution: 1M Na-acetate buffer (pH=4.2)
  • Reaction mixture: 10 μl enzyme solution
    • 10 μl test compound or assay buffer
    • 55 μl assay buffer
    • 25 μl substrate
    • 300 μl stop solution
  • Measurement: spectrofluorometric determination by Tecan plate reader
    • (Ex: 360 nm Em: 465 nm)
The reaction of the DPP-IV enzyme and the H-Gly-Pro-AMC substrate is recorded by the liberation of AMC (7-amino-4-methylcoumarin) at 37° C. in 100 mM Tris-HCl, pH=7.5 (assay buffer). Standard curve of AMC is linear up to 31.25 μM concentration, that is why we used the relative fluorescence unit (RFU) of the AMC formed. It is detected by using 360 nm excitation and 465 emission filters (30 μs integration time, Gain 25, No. of Flashes 50) by Tecan Spectrofluor Plus plate reader. Under these conditions enzyme reaction is linear for at least 30 min, and the enzyme dependence is linear up to 2.5 μg protein (up to 700 RFU). Using 1-0.8 μg of extracted protein Km for H-Gly-Pro-AMC is 50 μM. Substrate concentrations higher than 500 μM caused fluorescency detection problems (inner filter effect) that can be solved by dilution of the samples.
The assay is designed to detect the active inhibitors as efficiently as possible, using a 60 min preincubation time at 37° C. The assay is conducted by adding 0.8-1 μg protein extract in 10 μl enzyme solution (using assay buffer: 100 mM Tris-HCl, pH=7.5) to the wells containing the test compounds in 10 μl volume and the 55 μl assay buffer (65 μl assay buffer in the case of controls). After the preincubation period, the reaction is started by the addition of 25 μl 1 mM H-Gly-Pro-AMC substrate solution (250 μM final concentration). The final test volume is 100 μl and the test solution contains 1% DMSO coming from the test compounds solution. Reaction time is 30 min at 37° C., and the reaction is stopped by adding 300 μl 1M Na-acetate buffer, pH=4.2. The fluorescence (RFU) of AMC formed is detected using 360 nm excitation and 465 emission filters in Tecan spectrofluor Plus plate reader (30 μs integration time, Gain 25 No. of Flashes 50). Inhibition % are calculated using the RFU of control and RFU of blank.
IC50 values characteristic for the enzyme inhibitory effect of the compounds of the general formula (I) according to the invention are smaller than 100 nM.
The compounds of the general formula (I) and their salts solvates and isomers can be formulated to orally or parenterally applicable pharmaceutical compositions by methods known per se, by mixing them with one or more pharmaceutically accepted excipients and can be administered as a unitary dosage form.
The appropriate unitary dosage form comprise the oral forms, such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, the sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-cutaneous, intramuscular or intra-venous forms, the rectal forms and the implants. For the topical application, the compounds of the invention may be used as creams, gels, ointments of lotions.
As example, a unitary dosage form for a compound according to the invention, in the form of a tablet, can comprise the following ingredients:
A compound of the general formula (I) 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropyl methylcellulose 2.25 mg
Magnesium stearate 3.0 mg
Daily dose of the compounds of the general formula (I) may depend on several factors, thus the nature and seriousness of the disease of the patient, the mode of application and on the compound itself.
Further details of the invention are demonstrated by the examples below, without limiting the claims to the examples.
FIG. 1 shows compounds of the general formula (I),
FIG. 2 shows compounds of the general formula (II),
FIG. 3 shows compounds of the general formula (III),
FIG. 4 shows compounds of the general formula (IV),
FIG. 5 shows compounds of the general formula (V),
FIG. 6 shows compounds of the general formula (VI),
FIG. 7 shows compounds of the general formula (VII),
FIG. 8 shows compounds of the general formula (VIII),
FIG. 9 shows compounds of the general formula (IX),
FIG. 10 shows compounds of the general formula (X),
FIG. 11 shows formula (1),
FIG. 12 shows formula (2),
FIG. 13 shows formula (3),
FIG. 14 shows formula (4),
FIG. 15 shows formula (5),
FIG. 16 shows formula (6),
FIG. 17 shows formula (7).
 EXAMPLES Example 1 (2S)-4,4-difluoro-1-(2-{[8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl]exo-amino}acetyl)-2-pyrrolidine carbonitrile
The meaning of R1 is 2-pyrimidinyl group, B means a group of formula (4), R2 and R3 mean fluorine atom in general formula (I).
a.) tert-butyl 8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate with (V) General Formula—where R1 is 2-pyrimidinyl, Y is COOC(CH3)3, B is (4) Group
14.7 g of tert-butyl 8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate (65 mmol) (J. Med. Chem. 1991, 34, 656) and 8.93 g of 2-chloropyrimidine (78 mmol) and 12.7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (85 mmol) are dissolved in 230 ml of 1-pentanol and heated under reflux for 4 hours. The solvents are evapotared and the residue is dissolved in 250 ml of chloroform and washed with 2×300 ml of water, dried over Na2SO4, and purified by column chromatography using n-hexane-ethyl acetate-chloroform (1:1:1) as eluent to result in white crystals which are triturated with n-hexane. Yield: 13.25 g (67%). M.p.: 113-115° C. 1H-NMR (400 MHz, CDCl3): δ 1.34 (s, 9H), 1.49 (t, 2H), 1.66-1.97 (m, 6H), 3.89 (br, 1H), 4.61 (d, 2H), 6.60 (t+br, 1+1H), 8.34 (d, 2H).
b.) 8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-amine with (II) General Formula—where R1 and B are Given in Step 1a.)
13 g of tert-butyl 8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate (43 mmol) are dissolved in a mixture of 120 ml of trifluoroacetic acid and 120 ml of dichloromethane. The solution is stirred for 30 minutes and evaporated. The residue is dissolved in 50 ml of dichloromethane and evaporated. This method is repeated three times and the last organic solution is extracted with 100 ml of saturated aq. sodium carbonate solution. The layers are separated and the aqueous phase is washed with 4×50 ml of dichloromethane. The combined organic layers are dried over Na2SO4 and evaporated to result in a white powder which is triturated with n-hexane. Yield: 6.7 g (77%). M.p.: 56-59° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.29 (t, 2H), 1.64-1.98 (m, 6H), 3.19 (m, 1H), 4.58 (dd, 2H), 6.57 (t, 1H), 8.33 (d, 2H).
c.) tert-butyl) (2S)-2-(aminocarbonyl)-4,4-difluoro-1-pyrrolidinecarboxylate of the General Formula (VII) wherein R2 and R3 Mean Fluorine Atom
5.7 g (22.7 mmol) of tert-butyl (2S)-2-(aminocarbonyl)-4,4-difluoro-2-pyrrolidinecarboxylic acid (Tetraheron Lett. 1998, 39, 1169) are dissolved in 57 ml of dichloromethane and to the solution 3.8 ml (27.2 mmol) of triethylamine are added. To the resulting mixture dropwise, at −15° C. 3 ml (25 mmol) of pivaloyl chloride are added and the mixture is stirred at that temperature for 1 hour, then 7 ml of 25% aqueous ammonia solution are added drop wise and the mixture is stirred for 1 hour. The reaction mixture is washed with water, 1 N NaOH solution, then with water, dried over sodium sulphate and evaporated. On addition of diethyl ether 3.94 g (69%) of the above product crystallize. M.p.: 136-138° C. 1H-NMR (400 MHz, CDCl3): δ 1.48 (s, 9H); 2.3-2.9 (m, 3-CH2), 3.69 (br, minor)+3.86 (m, major)(5-CH2), 4.53 (br, 2-CH). 6.0 (br, major) +6.81 (br, minor)(NH2).
d.) (2S)-4,4-difluoro-2-pyrrolidinecarboxamide hydrochloride of the General Formula (VIII) wherein R2 and R3 Mean Fluorine Atoms
3.93 g (15.7 mmol) of tert-butyl (2S)-2-(aminocarbonyl)-4,4-difluoro-1-pyrrolidinecarboxylate are dissolved in 75 ml of 25% ethanolic hydrogen chloride solution and stirred at room temperature for 4 hours. To the resulting suspension 150 ml of diethyl ether are added, the resulting white crystalline material is filtered off. 2.55 g (87%) of the above product are obtained. M.p.: 232-233° C. 1H-NMR (400 MHz, DMSO-d6): δ 2.43-2.51 (m, minor) and 2.81-3.05 (m, major)(3-CH2), 3.71 (t, 2H, 5-CH2), 4.46 (t, 1H, 2-CH), 7.81 (s, 1H)+8.12 (s, 1H)(NH2), 10.12 (br, 2H, NH2 +).
e.) (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine-carboxamide of the General Formula (IX) wherein R2 and R3 Mean Fluorine Atoms
2.54 g (13.6 mmol) of (2S)-4,4-difluoro-2-pyrrolidinecarboxamide hydrochloride are suspended in 25 ml of dichloromethane and to the suspension 4.1 ml (29.3 mmol) of triethylamine are added. To the resulting mixture drop wise, below −10° C. 1.2 ml (15 mmol) of chloroacetyl chloride in 20 ml of dichloromethane are added. After 1 hour of stirring the suspension is poured into 450 ml of ethyl acetate, the precipitated triethylamine hydrochloride is filtered off, the filtrate is evaporated and purified by chromatography using chloroform—methanol 4:1 mixture eluent. 3.0 g (97%) of the above product are obtained in the form of colourless oil. 1H-NMR (400 MHz, DMSO-d6): δ 2.34-2.52 (m, 1H) +2.66-2.83 (m, 1H)(3-CH2), 4.07-4.29 (m, 2H, 5-CH2), 4.40 (qv, 2H, CH2Cl), 4.71 (m, 1H, 2-CH), 7.17 (br, 1H)+7.42 (d, 1H)(NH2).
f.) (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidinecarbonitrile of the General Formula (III) wherein R2 and R3 Mean Fluorine Atoms
10.4 g (46 mmol) of (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine-carboxamide are dissolved in 230 ml of dichloromethane and 13 ml (140 mmol) of phosphorous oxychloride are added thereto. The mixture is heated for 24 hours (if there is remaining starting material then it is refluxed further). During the refluxing the solution will become pale yellow and sticky solid material is precipitated. The solution is poured into another pot and 50 g of potassium carbonate are added thereto. After stirring for an hour the solid salts are filtered out and the solution is evaporated. Pale yellow oil is received which is triturated with n-hexane. The received yellow crystals are collected and 70 ml of diethyl-ether are added. Thus impurities are dissolved and pure white solid crystalline product is obtained. Yield: 6.0 g (56%). M.p.: 86-87° C. 1H-NMR (400 MHz, CDCl3): δ 2.76-2.98 (m, 2H, 3-CH2), 3.92-4.26 (m, 2H, 5-CH2), 4.46 (qv, 2H, CH2Cl), 5.11 (m, 1H, 2-CH).
g.) (2S)-4,4-difluoro-1-(2-{[8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl]exo-amino}acetyl)-2-pyrrolidinecarbonitrile
6.13 g of 8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-amine (30 mmol) and 5.74 g of (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidinecarbo-nitrile (27.5 mmol) and 12.5 ml of triethylamine (90 mmol) are dissolved in 250 ml of dry acetonitrile and stirred at 70° C. for 3 hours and then at room temperature overnight. Then the mixture was evaporated to give a brownish thick oil which is purified by column chromatography using chloroform-methanol (6:1) as the eluent to result in a solid product which is crystallized from abs. ethanol. Yield: 5.7 g (77%). M.p.: 162-163° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.32 (td, 2H), 1.6-2.0 (m, 7H), 2.6-2.9 (m, 2H), 2.85 (tt, 1H), 3.0-3.5 (m, 2H), 3.97 (ddd, 1H), 4.13 (ddd, 1H), 4.61 (m, 2H), 5.05 (dd, 1H), 6.60 (t, 1H), 8.35 (m, 2H).
Example 2 (2S,4S)-4-fluoro-1-(2-{[8-(2-pyrazinyl)-8-azabicyclo-[3.2.1]-oct-3-yl]exo-amino}acetyl)-2-pyrrolidinecarbonitrile dihydrochloride
In the general formula (I) R1 means 2-pyrazinyl-group, B means a group of formula (4), R2 means hydrogen atom and R3 means fluorine atom.
a.) tert-butyl 8-(2-pyrazinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate with (V) General Formula—where R1 is 2-pyrazinyl, Y is COOC(CH3)3, B is (4) Group
0.54 ml of chloropyrazine (6 mmol) and 1.13 g of tert-butyl 8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate (6 mmol) 0.97 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.5 mmol) are dissolved in 40 ml of 1-pentanol and heated under reflux for 50 hours. The solvents are evapotared, the residue is dissolved in 50 ml of chloroform, washed with 4×30 ml of water, dried over Na2SO4, and purified by column chromatography using n-hexane-ethyl acetate-chloroform (3:1:1) as eluent to result in white crystals which are triturated with n-hexane. Yield: 0.55 g (36%). M.p.: 122-123° C. 1H-NMR (200 MHz, DMSO-d6): δ 1.34 (s, 9H); 1.44-1.66 (m; 2H), 1.67-1.99 (m, 6H), 3.88 (m, 1H), 4.56 (bs, 2H), 6.59 (d, 1H), 7.77 (d, 1H), 8.07 (dd, 1H), 8.17 (d, 1H).
b.) 8-(2-pyrazinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-amine with (II) General Formula—where R1 and B are Given in Step 2a.)
3.85 mg of tert-butyl 8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-carbamate (1.26 mmol) are dissolved in 20 ml of 12% ethanolic hydrochloric acid and the solution is stirred for 7 hours. 20 ml water is added to the formed suspension and the pH is made to 11 with aqueous potassium hydroxide. The layers are separated, the organic phase are dried, evaporated and purified by column chromatography using ethyl acetate—methanol—25% aqueous NH3 solution (17:3:1) as eluent to result in a pale yellow oil. Yield is 167 mg (65%). 1H-NMR (200 MHz, DMSO-d6): δ 1.29 (t, 2H), 1.62-1.83 (m, 4H), 1.84-2.00 (m, 2H), 3.12 (sp, 1H), 4.57 (dd, 2H), 7.74 (d, 1H), 8.05 (dd, 1H), 8.15 (d, 1H).
c.) tert-butyl (2S,4S)-2-(aminocarbonyl)-4-fluoro-1-pyrrolidinecarboxylate of the General Formula (VII) wherein R2 Means Hydrogen Atom and R3 Means Fluorine Atom
1.63 g (7 mmol) of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinecarboxylic acid (Tetraheron Lett. 1998, 39, 1169) are dissolved in 25 ml of dichloromethane and 1.2 ml (8.4 mmol) of triethylamine are added. 0.86 ml (7 mmol) of pivaloyl chloride are added dropwise to the mixture at −15° C. and it is stirred for 1 hour and 2 ml 25% of aqueous ammonium-hydroxide solution are added thereto. After one hour of stirring the reaction mixture is washed with water, 1N sodium hydroxide solution and with water again, it is dried on sodium sulfate and evaporated. 0.88 g (54%) of the title compound is crystallized from diethylether. Melting point is 173-175° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.38 (s, 9H); 2.07-2.25 (m, 2H, 3-CH2), 3.49-3.67 (m, 2H, 5-CH2), 4.13 (d, 1H, 2-CH), 5.07 and 5.35 (br, 1H, 4-H), 6.91+7.17 (br, 2H, NH2).
d.) (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride
In the general formula (VIII) R2 means hydrogen atom and R3 means fluorine atom.
4 g (17.2 mmol) of tert-butyl (2S,4S)-2-(aminocarbonyl)-4-fluoro-1-pyrrolidinecarboxylate are dissolved in 75 ml of 25% ethanolic hydrogen chloride solution and it is stirred for 4 hours at room temperature. The obtained white crystalline substance is filtered off, washed with ether and dried. Thus 2.56 g (88%) of above product are obtained. M.p.: 250-251° C. 1H-NMR (400 MHz, DMSO-d6): δ 2.31 (t, 1H), 2.49-2.65 (m, 1H), 3.46 (m, 1H), 4.30 (dd, 1H), 5.37 (d, 1H), 7.71 (s, 1H) and 8.09 (s, 1H) (NH2), 9.7 (br, 2H, NH2 +).
e.) (2S,4S)-1-(2-chloroacetyl)-4-fluoro-2-pyrrolidinecarboxamide
In the general formula (IX) R2 means hydrogen atom and R3 means fluorine atom. 2.54 g (15 mmol) of (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride are suspended in 60 ml of dichloromethane and 4.6 ml (33 mmol) of triethylamine are added thereto. To the obtained mixture, 1.27 ml (16 mmol) of chloroacetyl chloride dissolved in 15 ml of dichloromethane are added dropwise below −10° C. The reaction mixture is stirred for an hour and the suspension is poured into 500 ml of ethylacetate, the precipitated triethylamine hydrochloride is filtered off, the filtrate is concentrated and purified by chromatography using a chloroform-methanol 4:1 mixture.
Thus 3.0 g (97%) of title compound are obtained as a colourless oil which crystallizes during standing. Its melting point is 95-96° C. 1H-NMR (400 MHz, DMSO-d6): δ 2.22-2.50 (m, 2H, 3-CH2), 3.57-4.04 (m, 2H, 5-CH2), 4.36 (qv, 2H, CH2Cl), 5.22 (d, 0.5H) and 5.39 (d, 0.5H) (4-CH), 7.03 (s, 0.74H) and 7.22 (s, 1H) and 7.56 (s, 0.26H) (NH2).
f.) (2S,4S)-1-(2-chloroacetyl)-4-fluoro-2-ppyrrolidinecarbonitrile
In the general formula (III) R2 means hydrogen atom and R3 means fluorine atom.
1.73 g (46 mmol) of (2S,4S)-1-(2-chloroacetyl)-4-fluoro-2-pyrrolidinecarboxamide are dissolved in a mixture of 20 ml of dry acetonitrile and 30 ml of dry dichloromethane and 32 ml (25 mmol) of phosphorous oxychloride are added thereto. The mixture is refluxed for 24 hours. The solution is poured into another flask and 50 g of potassium carbonate are added and the mixture is stirred for an hour. Solid salts are filtered off and after evaporation of the filtrate a pale yellow oil is obtained which is purified by chromatography using a 9:1 mixture of chloroform and methanol. The pure above product is 0.6 g (43%) white crystalline solid. M.p.: 134-136° C. 1H-NMR (400 MHz, CDCl3): δ 2.23-2.62 (m, 2H, 3-CH2), 3.59-4.06 (m, 2H, 5-CH2), 4.46 (qv, 2H, CH2Cl), 4.99 (m, 1H, 2-CH), 5.36 (m, 0.5H) and 5.64 (m, 0.5H) (4-H).
g.) (2S,4S)-4-fluoro-1-(2-{[8-(2-pyrazinyl)-8-azabicyclo[3.2.1]octan-3-yl]exoamino}acetyl-2-pyrrolidinecarbonitrile dihydrochloride of general formula (I) wherein R1 means 2-pyrazinyl group, B means a group of formula (4), R2 stands for hydrogen atom and R3 stands for fluorine atom.
243 mg (1.2 mmol) of 8-(2-pyrazinyl)-8-azabicyclo[3.2.1]oct-3-yl-exo-amine reacted with 191 mg (1 mmol) of (2S,4S)-1-(2-chloroacetyl)-4-fluoro-2-pyrrolidine carbonitrile as it is described in Example 1/g.). The product is purified by chromatography using a 4:1 mixture of chloroform and methanol and its dihydrochloride is prepared. Thus 125 mg (29%) of title compound are obtained in the form of white crystals. M.p.: 201-202° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.76-1.80 (m, 4H), 1.94-2.01 (m, 4H), 2.47-2.51 (m, 2H), 3.64-3.80 (m, 1H), 3.79-4.03 (m, 2H), 4.15 (m, 1H), 4.67 (m, 2H), 5.03 (m, 1H), 5.52 (d, 1H), 7.86 (s, 1H), 8.15 (dd, 1H), 8.28 (d, 2H), 8.90 and 9.00 (s, 2H).
Example 3 (2S)-4,4-Difluoro-1-(2-{[1-(2-pyrazinyl) piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile dihydrochloride
The meaning of R1 is 2-pyrazinyl group, B means a group of formula (I), R2 and R3 mean fluorine atom in general formula (I).
a.) 1-(2-Pyrazinyl)-4-acetamino-piperidine with (V) General Formula—where R1 is 2-pyrazinyl, Y is COCH3, B is (1) Group
0.45 ml of chloropyrazine (5 mmol) and 1.6 g of 4-acetaminopyperidine (10 mmol) are dissolved in 15 ml of 1-pentanol and heated under reflux for 14 hours. The solvent are evaporated and the residue is purified by column chromatography using ethyl acetate—methanol—25% aqueous NH3 solution (17:3:1) as eluent to result 0.81 g (76%) of the above crystalline product. M.p.: 158-160° C. 1H-NMR (200 MHz, DMSO-d6): δ 1.34 (dq, 2H), 1.78 (m, 5H), 3.03 (dt, 2H), 3.74-3.89 (m, 1H), 4.21 (td, 2H), 7.77 (d, 1H, 3′-H), 7.80 (s, 1H, NH), 8.05 (dd, 1H, 5′-H), 8.31 (d, 1H, 6′-H).
b.) 1-(2-Pyrazinyl)-4-amino-piperidine with (II) General Formula—where R1 and B are Given in Step 3a.).
697 mg of 1-(2-Pyrazinyl)-4-acetamino-piperidine (3.2 mmol) are dissolved in 15 ml of 2 N hydrochloric acid and the solution is heated under reflux for 8 hours. After cooling the mixture is treated with 20% sodium hydroxide and the aqueous solution washed with 4×20 ml dichloromethane. The combined organic layers are dried over Na2SO4 and evaporated to afford 292 mg (52%) of the above product as yellow crystals. M.p.: 113-115° C. 1H-NMR (200 MHz, DMSO-d6-CDCl3): δ 1.09-1.36 (m, 2H), 1.78 (d, 2H), 2.78-3.31 (m, 4H), 3.54 (m, 1H), 7.76 (d, 1H, 3′-H), 8.03 (dd, 1H, 5′-H), 8.29 (d, 1H, 6′-H).
c.) (2S)-4,4-Difluoro-1-(2-{[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidinecarbonitrile dihydrochloride of General Formula (I) wherein R1 is 2-pyrazinyl group, B Means a Group of Formula (I), R2 and R3 Mean Fluorine Atom
63 mg of 1-(2-pyrazinyl)-4-amino-piperidine (0.32 mmol) and 62 mg (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine carbonitrile (0.32 mmol) and 285 mg of polymer-bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) (0.73 mmol) are dissolved in 20 ml dry acetonitrile and stirred at 55° C. for 8 hours. The resin is removed by filtration, the filtrate is concentrated by vacuum and the residue is purified by column chromatography using chloroform—methanol (9:1) as eluent to result an oil, which is treated with hydrochloric acid in diethylether result in 83 mg (60%) of title compound, as white crystals. M.p.: 158-160° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4.20-4.25 (m, 4H), 4.55 (d, 2H), 5.20 (t, 1H), 7.00 (d, 1H), 7.87 (dd, 1H), 8.50 (d, 1H); 9.38 (br, 2H).
Example 4 (2S)-4,4-Difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile dihydrochloride
The meaning of R1 is 5-cyano-pyridin-2-yl group, B means a group of formula (I), R2 and R3 mean fluorine atom in general formula (I).
a.) 1-(5-Cyanopyridin-2-yl)-4-acetamino-piperidine with (V) General Formula—where R1 is 5-cyanopyridin-2-yl, Y is COCH3, B is (1) Group
Following procedures outlined for examples 3a), the above crystalline product is isolated. Melting point is 246-251° C. 1H-NMR (200 MHz, DMSO-d6): δ 1.19-1.39 (m, 2H), 1.82 (m, 5H), 3.04-3.18 (m, 2H), 3.85 (m, 1H), 4.29 (dd, 2H), 6.94 (d, 1H), 7.82 (dd, 1H), 8.46 (d, 1H).
b.) 1-(5-Cyanopyridin-2-yl)-4-amino-piperidine with (II) General Formula—where R1 and B are Given in Step 4a.).
Following procedures outlined for examples 3b), the above crystalline product is isolated. M.p.: 65-68° C. 1H-NMR (200 MHz, CDCl3-DMSO-d6): δ 1.16-1.38 (m, 2H), 1.83-1.92 (m, 2H), 2.89-3.06 (m, 2H), 4.26 (dd, 2H), 6.54 (d, 1H), 7.50 (dd, 1H), 8.29 (d, 1H).
c.) (2S)-4,4-Difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidinecarbonitrile dihydrochloride
Following procedures outlined for examples 3c), the above crystalline product is isolated. M.p.: 146-147° C. 1H-NMR (DMSO-d6): δ 1.56 (m, 2H), 2.15 (d, 2H), 2.92 (m, 4H), 4.20 (m, 4H), 4.55 (d, 2H), 5.20 (t, 2H), 7.01 (d, 1H), 7.88 (d, 1H), 8.49 (dd, 1H), 9.38 (d, 2H).
Following procedures, outlined for Examples 1-2, the compounds listed in the Table 1 were prepared as a free base or as a salt.
TABLE 1
(I)
Figure US07655663-20100202-C00004
B Melting point, composition,
Example R1 (Formula) R2 R3 physical appearance
5.
Figure US07655663-20100202-C00005
 		(4) F F 133-141° C., dihydrochloride, off-white crystals
6.
Figure US07655663-20100202-C00006
 		(4) F F 238-240° C., dihydrochloride, yellow crystals
7.
Figure US07655663-20100202-C00007
 		(4) F F 237-239° C., dihydrochloride white crystals
8.
Figure US07655663-20100202-C00008
 		(4) F F 160-162° C., yellow crystals
9.
Figure US07655663-20100202-C00009
 		(4) F F 119-121° C., dihydrochloride, white crystals
10.
Figure US07655663-20100202-C00010
 		(4) F F 221-225° C., trihydrochloride, white crystals
11.
Figure US07655663-20100202-C00011
 		(4) F F 200-201° C., dihydrochloride, white crystals
12.
Figure US07655663-20100202-C00012
 		(4) F F 185-189° C., dihydrochloride, white crystals
13.
Figure US07655663-20100202-C00013
 		(4) F F 108-110° C., white crystals
14.
Figure US07655663-20100202-C00014
 		(4) F F >340° C., dihydrochloride, off-white crystals
15.
Figure US07655663-20100202-C00015
 		(4) F F 300-305° C., dihydrochloride white crystals
16.
Figure US07655663-20100202-C00016
 		(4) F F 185-186° C., dihydrochloride, yellow crystals
17.
Figure US07655663-20100202-C00017
 		(4) F F 293-296° C., dihydrochloride, white crystals
18.
Figure US07655663-20100202-C00018
 		(4) F F 148-167° C., dihydrochloride, white solid
19.
Figure US07655663-20100202-C00019
 		(4) F F >350° C., 1.5 HCl, white crystals
20.
Figure US07655663-20100202-C00020
 		(4) F F 240-243° C., dihydrochloride, white crystals
21.
Figure US07655663-20100202-C00021
 		(4) F F 102-104° C., white crystals
22.
Figure US07655663-20100202-C00022
 		(4) F F 236-241° C., trihydrochloride, white crystals
23.
Figure US07655663-20100202-C00023
 		(4) F F 201-202° C., dihydrochloride, white crystals
24.
Figure US07655663-20100202-C00024
 		(4) F F 256-259° C., dihydrochloride, white crystals
25.
Figure US07655663-20100202-C00025
 		(4) F F 119-120° C., yellow crystals
26.
Figure US07655663-20100202-C00026
 		(4) F F 114-117° C., white solid
27.
Figure US07655663-20100202-C00027
 		(4) F F 94-97° C., white solid
28.
Figure US07655663-20100202-C00028
 		(2) F F 66-70° C., white foam
29.
Figure US07655663-20100202-C00029
 		(3) F F 216-218° C., dihydrochloride, white crystals
30.
Figure US07655663-20100202-C00030
 		(5) F F 182-185° C., white solid
31.
Figure US07655663-20100202-C00031
 		(5) F F 241-243° C., trihydrochloride, yellow crystals
32.
Figure US07655663-20100202-C00032
 		(6) F F 276-278° C., dihydrochloride, yellow crystals
33.
Figure US07655663-20100202-C00033
 		(6) F F 240-243° C., dihydrochloride, yellow crystals
34.
Figure US07655663-20100202-C00034
 		(6) F F 82-85° C., hydrochlorid, off-white crytals
35.
Figure US07655663-20100202-C00035
 		(7) F F 141-144° C., white crystals
36.
Figure US07655663-20100202-C00036
 		(7) F F 281-284° C., dihydrochloride, yellow crystals
37.
Figure US07655663-20100202-C00037
 		(7) F F 271-272° C., dihydrochloride, off-white crytals
Following procedures, outlined for Examples 3-4, the compounds listed in the Table 2 were prepared as a free base or as a salt.
TABLE 2
(I)
Figure US07655663-20100202-C00038
B Melting point, composition,
Example R1 (Formula) R2 R3 physical appearance
38.
Figure US07655663-20100202-C00039
 		(1) F F 219-228° C., dihydrochloride, white crystals
39.
Figure US07655663-20100202-C00040
 		(1) F F 198-200° C., dihydrochloride, white crystals
40.
Figure US07655663-20100202-C00041
 		(1) F F 224-229° C., trihydrochloride, off white crystals
41.
Figure US07655663-20100202-C00042
 		(1) H F 157-158° C., pale yellow crystals
42.
Figure US07655663-20100202-C00043
 		(1) F F 2.5 HCl, amorphous white solid
43
Figure US07655663-20100202-C00044
 		(1) F F 292-295° C., dihydrochloride, white crystals
44.
Figure US07655663-20100202-C00045
 		(1) F F 210-212° C., dihydrochloride, white crystals
45.
Figure US07655663-20100202-C00046
 		(1) F F 284-288° C., dihydrochloride, white crystals
46.
Figure US07655663-20100202-C00047
 		(1) F F 282-285° C,, dihydrochloride, off white crystals
47.
Figure US07655663-20100202-C00048
 		(1) F F 170-173° C., dihydrochloride; yellow crystals
48.
Figure US07655663-20100202-C00049
 		(1) H F 122-124° C., white crystals
49.
Figure US07655663-20100202-C00050
 		(1) F F 102-105° C., dihydrochloride, white crystals
50.
Figure US07655663-20100202-C00051
 		(1) F F 63-65° C., white crystals
51.
Figure US07655663-20100202-C00052
 		(1) F F >350° C., dihydrochloride, white crystals
52.
Figure US07655663-20100202-C00053
 		(1) F F 168-171° C., dihydrochloride, white crystals
53.
Figure US07655663-20100202-C00054
 		(1) F F 173-175° C., dihydrochloride, yellow crystals
54.
Figure US07655663-20100202-C00055
 		(1) F F 162-163° C., dihydrochloride, white crystals
55
Figure US07655663-20100202-C00056
 		(1) F F Dihydrochloride, amorphous off-white solid
56.
Figure US07655663-20100202-C00057
 		(1) F F 51-53° C., light yellow foam
57.
Figure US07655663-20100202-C00058
 		(1) F F 228-230° C., dihydrochloride, white crystals
58.
Figure US07655663-20100202-C00059
 		(1) F F 281-284° C., dihydrochloride, yellow crystals
59.
Figure US07655663-20100202-C00060
 		(1) F F 116-120° C., dihydrochloride, yellow crystals
60.
Figure US07655663-20100202-C00061
 		(1) F F 178-185° C., salt formed with 2.5 molecules of HCl, white crystals
61.
Figure US07655663-20100202-C00062
 		(1) F F Dihydrochloride, amorphous off-white solid
62.
Figure US07655663-20100202-C00063
 		(1) F F 226-235° C., dihydrochloride, white crystals
63.
Figure US07655663-20100202-C00064
 		(1) F F 278-283° C., dihydrochloride, off-white crystals
64.
Figure US07655663-20100202-C00065
 		(1) F F 2,5 HCl, amorphous yellow solid
65.
Figure US07655663-20100202-C00066
 		(1) F F 318-320° C., dihydrochloride, white crystals
66.
Figure US07655663-20100202-C00067
 		(1) F F 157-160° C., white crystals
Following procedures, outlined for Examples 1-4, the compounds of the general formula (I) listed in the Table 3 were prepared as a free base or as a salt.
TABLE 3
(I)
Figure US07655663-20100202-C00068
B Melting point, composition,
Example R1 (Formula) R2 R3 physical appearance
67.
Figure US07655663-20100202-C00069
 		(1) F F 216-228° C., trihydrochloride, off white crystals
68.
Figure US07655663-20100202-C00070
 		(1) F F 163-167° C., cream-coloured solid
69.
Figure US07655663-20100202-C00071
 		(1) F F dihydrochloride, amorphous off-white solid
70.
Figure US07655663-20100202-C00072
 		(1) F F 275-277° C., dihydrochloride, white solid
71.
Figure US07655663-20100202-C00073
 		(4) F F 148-152° C., dihydrochloride, pale yellow crystals
72.
Figure US07655663-20100202-C00074
 		(7) F F 229-231° C., trihydrochloride, white crystals
Following procedures outlined for Examples 1a) and 2a) the intermediate compounds of the general formula (V) listed in the Table 4 were prepared.
TABLE 4
(V)
Figure US07655663-20100202-C00075
Characterisation (M.p., LC/MS or
Example R1 aromatic protons 1H-NMR [DMSO-d6]
4.1.
Figure US07655663-20100202-C00076
 		6.93 (m, 1 H), 7.35 (m, 1 H), 7.98 (m, 1 H), 8.04 (d, 1 H)
4.2.
Figure US07655663-20100202-C00077
 		141-143° C.
4.3.
Figure US07655663-20100202-C00078
 		212-215° C.
4.4.
Figure US07655663-20100202-C00079
 		6.58 (d, 1 H), 6.65 (d, 1 H), 7.51 (t, 1 H)
4.5.
Figure US07655663-20100202-C00080
 		2.37 (s, 3 H), 6.75 (1 H, d), 7.15 (1 H, dd), 7.81 (1 H, d)
4.6.
Figure US07655663-20100202-C00081
 		6.75 (d, 1 H), 7.60 (d, 1 H), 8.12 (s, 1 H)
4.7.
Figure US07655663-20100202-C00082
 		6.65 (d, 1 H), 7.84 (d, 1 H)
4.8.
Figure US07655663-20100202-C00083
 		227-230° C.
4.9.
Figure US07655663-20100202-C00084
 		7.30 (d, 1 H), 7.51 (d, 1 H)
4.10.
Figure US07655663-20100202-C00085
 		6.71 (d, 1 H), 8.31 (d, 1 H)
4.11.
Figure US07655663-20100202-C00086
 		161-162° C.
4.12.
Figure US07655663-20100202-C00087
 		6.72 (d, 1 H), 8.04 (d, 1 H)
4.13.
Figure US07655663-20100202-C00088
 		187-188° C.
4.14.
Figure US07655663-20100202-C00089
 		[MH]+ = 330
4.15.
Figure US07655663-20100202-C00090
 		172-174° C.
4.16.
Figure US07655663-20100202-C00091
 		6.80 (d, 1 H), 7.19 (d, 1 H)
4.17.
Figure US07655663-20100202-C00092
 		6.87 (d, 1 H), 7.20 (td, 1 H), 7.61 (m, 1 H), 7.57 (m, 2H), 7.86 (d, 1 H)
4.18.
Figure US07655663-20100202-C00093
 		7.38 (td, 1 H), 7.57 (td, 1 H), 7.74 (dd, 1 H), 7.88 (dd, 1 H), 8,45 (s, 1 H)
4.19.
Figure US07655663-20100202-C00094
 		7.16 (t, 1 H), 7.35 (t, 1 H), 7.53 (d, 1 H), 7.86 (d, 1 H)
4.20.
Figure US07655663-20100202-C00095
 		163-165° C.
4.21.
Figure US07655663-20100202-C00096
 		166-169° C.
4.22.
Figure US07655663-20100202-C00097
 		153-156° C.
4.23.
Figure US07655663-20100202-C00098
 		7.51 (m, 5 H)
Following procedures outlined for Examples 1a) and 2a) the intermediate compounds of the general formula (V) listed in the Table 5 were prepared.
TABLE 5
(V)
Figure US07655663-20100202-C00099
Characterisation (M.p.
B or aromatic protons
Example R1 (Formula) by 1H-NMR [DMSO-d6]
5.1.
Figure US07655663-20100202-C00100
 		(2) 154-156° C.
5.2.
Figure US07655663-20100202-C00101
 		(5) 134-135° C.
5.3.
Figure US07655663-20100202-C00102
 		(5) 159-161° C.
5.4.
Figure US07655663-20100202-C00103
 		(6) 7.82 (d, 1 H), 8.11 (d, 1 H), 8.35 (s, 1 H)
5.5.
Figure US07655663-20100202-C00104
 		(6) 6.93 (d, 1 H), 7.91 (d, 1 H), 8.54 (s, 1 H)
5.6.
Figure US07655663-20100202-C00105
 		(6) 6.99 (t, 1 H), 7.13 (t, 1 H), 7.26 (d, 1 H), 7.36 (d, 1 H)
5.7.
Figure US07655663-20100202-C00106
 		(7) 6.50 (t, 1 H), 8.33 (m, 2H)
5.8.
Figure US07655663-20100202-C00107
 		(7) 6.90 (d, 1 H), 7.80 (d, 1 H), 8.44 (s, 1 H)
5.9.
Figure US07655663-20100202-C00108
 		(7) 6.98 (t, 1 H), 7.12 (t, 1 H), 7.29 (d, 1 H), 7.39 (d, 1 H)
5.10.
Figure US07655663-20100202-C00109
 		(7) 176-176° C.
Following procedures outlined for Examples 3a) and -4a) the intermediate compounds of the general formula (V) listed in the Table 6. were prepared (Y=Ac(acetyl) or Boc=tert butyloxy-carbonyl).
(V)
Figure US07655663-20100202-C00110
Characterisation (M.p., LC/MS or
Example R1 Y aromatic protons by 1H-NMR [DMSO-d6])
6.1.
Figure US07655663-20100202-C00111
 		Ac 6.60 (dd, 1 H), 6.67 (d, 1 H), 7.48 (td, 1 H), 8.17 (dd, 1 H)
6.2.
Figure US07655663-20100202-C00112
 		Boc 127-129° C.
6.3.
Figure US07655663-20100202-C00113
 		Boc 138-140° C.
6.4.
Figure US07655663-20100202-C00114
 		Ac 2.12 (s, 3H), 6.74 (d, 1 H), 7.33 (dd, 1 H), 7.76 (d, 1 H)
6.5.
Figure US07655663-20100202-C00115
 		Ac 166-164° C.
6.6.
Figure US07655663-20100202-C00116
 		Boc 6.58 (d, 1 H), 6.65 (d, 1 H), 7.51 (t, 1 H)
6.7.
Figure US07655663-20100202-C00117
 		Ac 6.65 (d, 1 H), 7.45 (dd, 1 H), 8.10 (d, 1 H)
6.8.
Figure US07655663-20100202-C00118
 		Ac 6.72 (d, 1 H), 7.60 (d, 1 H), 8.13 (s, 1 H)
6.9.
Figure US07655663-20100202-C00119
 		Ac 223-226° C.
6.10.
Figure US07655663-20100202-C00120
 		Boc 139-140° C.
6.11.
Figure US07655663-20100202-C00121
 		Ac 126-128° C.
6.12.
Figure US07655663-20100202-C00122
 		Boc 6.95 (d, 1 H), 7.22 (d, 1 H)
6.13.
Figure US07655663-20100202-C00123
 		Boc 169-171° C.
6.14.
Figure US07655663-20100202-C00124
 		Boc 144-146° C.
6.15.
Figure US07655663-20100202-C00125
 		Boc 172-174° C.
6.16.
Figure US07655663-20100202-C00126
 		Boc 149-152° C.
6.17.
Figure US07655663-20100202-C00127
 		Boc [MH]+ = 304
6.18.
Figure US07655663-20100202-C00128
 		Ac 196-200° C.
6.19.
Figure US07655663-20100202-C00129
 		Ac 6.80 (d, 1 H), 7.12 (d, 1 H)
6.20.
Figure US07655663-20100202-C00130
 		Ac 234-236° C.
6.21.
Figure US07655663-20100202-C00131
 		Ac 163-166° C.
6.22.
Figure US07655663-20100202-C00132
 		Boc 7.59 (m, 3 H), 8.10 (m, 1 H), 8.29 (d, 1 H)
6.23.
Figure US07655663-20100202-C00133
 		Boc 129-133° C.
6.24.
Figure US07655663-20100202-C00134
 		Boc 7.49 (d, 1 H), 7.72 (td, 1 H), 7.85 (td, 1 H), 7.90 (t, 1 H), 7.98 (d, 1 H), 8.13 (d, 1 H)
6.25.
Figure US07655663-20100202-C00135
 		Boc 7.38 (td, 1 H), 7.57 (td, 1 H), 7.74 (dd, 1 H), 7.88 (dd, 1 H), 8.45 (s, 1 H)
6.26.
Figure US07655663-20100202-C00136
 		Ac 7.01 (t, 1 H), 7.27 (t, 1 H), 7.42 (d, 1 H), 7.73 (d, 1 H)
6.27.
Figure US07655663-20100202-C00137
 		Boc 165-166° C.
6.28.
Figure US07655663-20100202-C00138
 		Boc 206-211° C.
6.29.
Figure US07655663-20100202-C00139
 		Boc 7.5 (m, 5 H)
6.30.
Figure US07655663-20100202-C00140
 		Boc 159-160° C.
Following procedures outlined for Examples 1b) and 2b) the intermediate compounds of the general formula (II) listed in the Table 7. were prepared.
TABLE 7
(II)
Figure US07655663-20100202-C00141
Characterisation (M.p.
or aromatic protons
by 1H-NMR
Example R1 [DMSO-d6])
7.1.
Figure US07655663-20100202-C00142
 		6.96 (m, 1 H), 7.34 (m, 1 H), 8.02 (m, 1 H), 8.08 (d, 1 H)
7.2.
Figure US07655663-20100202-C00143
 		123-125° C.
7.3.
Figure US07655663-20100202-C00144
 		175-178° C.
7.4.
Figure US07655663-20100202-C00145
 		6.55 (d, 1 H), 6.63 (d, 1 H), 7.49 (t, 1 H)
7.5.
Figure US07655663-20100202-C00146
 		2.40 (s, 3 H), 6.82 (dd, 1 H,), 7.20 (d, 1 H), 7.89 (d, 1 H)
7.6.
Figure US07655663-20100202-C00147
 		6.40 (d, 1 H), 7.60 (d, 1 H), 8.14 (s, 1 H)
7.7.
Figure US07655663-20100202-C00148
 		2.35 (s, 3 H), 6.62 (d, 1 H), 7.81 (d, 1 H)
7.8.
Figure US07655663-20100202-C00149
 		120-123° C.
7.9
Figure US07655663-20100202-C00150
 		7.32 (d, 1 H), 7.58 (d, 1 H),
7.10.
Figure US07655663-20100202-C00151
 		6.68 (d, 1 H), 8.29 (d, 1 H)
7.11.
Figure US07655663-20100202-C00152
 		7.77 (s, 1 H), 8.13 (s, 1 H)
7.12.
Figure US07655663-20100202-C00153
 		6.69 (d, 1 H), 8.02 (d, 1 H)
7.13.
Figure US07655663-20100202-C00154
 		194-198° C.
7.14.
Figure US07655663-20100202-C00155
 		115-117° C.
7.15.
Figure US07655663-20100202-C00156
 		2.40 (s, 3H), 6.40 (d, 1 H), 7.87 (d, 1 H)
7.16.
Figure US07655663-20100202-C00157
 		6.79 (d, 1 H), 7.12 (d, 1 H)
7.17
Figure US07655663-20100202-C00158
 		6.86 (d, 1 H), 7.19 (td, 1 H), 7.52 (m, 2 H), 7.69 (dd, 1 H), 7.84 (d, 1 H)
7.18
Figure US07655663-20100202-C00159
 		7.35 (m, 1 H), 7.58 (m, 1 H,), 7.80 (dd, 1 H), 8.66 (s, 1 H)
7.19
Figure US07655663-20100202-C00160
 		126-127° C.
7.20.
Figure US07655663-20100202-C00161
 		127-129° C.
7.21.
Figure US07655663-20100202-C00162
 		90-93° C.
7.22
Figure US07655663-20100202-C00163
 		107-107° C.
7.23.
Figure US07655663-20100202-C00164
 		227-228° C. as dihydrochloride
Following procedures outlined for Examples 1b) and 2b) the intermediate compounds of the general formula (II) listed in the Table 8 were prepared.
TABLE 8
R1—B—NH2 (II)
Characterisation (M.p.
B or aromatic protons
Example R1 (Formula) by 1H-NMR [DMSO-d6])
8.1.
Figure US07655663-20100202-C00165
 		(2) 6.49 (d, 1 H), 7.76 (dd, 1 H), 8.43 (d, 1 H)
8.2.
Figure US07655663-20100202-C00166
 		(5) 85-89° C.
8.3.
Figure US07655663-20100202-C00167
 		(5) 7.74 (d, 1 H), 8.04 (d, 1 H), 8.15 (s, 1 H)
8.4.
Figure US07655663-20100202-C00168
 		(6) 7.80 (d, 1 H), 8.12 (d, 1 H), 8.37 (s, 1 H)
8.5.
Figure US07655663-20100202-C00169
 		(6) 6.95 (d, 1 H), 7.89 (d, 1 H), 8.51 (s, 1 H)
8.6.
Figure US07655663-20100202-C00170
 		(6) 7.00 (t, 1 H), 7.14 (t, 1 H), 7.26 (d, 1 H), 7.37 (d, 1 H)
8.7.
Figure US07655663-20100202-C00171
 		(7) 6.50 (t, 1 H), 8.29 (d, 1 H), 8.31 (d, 1 H)
8.8.
Figure US07655663-20100202-C00172
 		(7) 6.90 (d, 1 H), 7.80 (d, 1 H), 8.47 (s, 1 H)
8.9.
Figure US07655663-20100202-C00173
 		(7) 6.95 (t, 1 H), 7.14 (t, 1 H), 7.26 (d, 1 H), 7.37 (d, 1 H)
8.10.
Figure US07655663-20100202-C00174
 		(7) 3.83 (s, 2 H), 7.21-7.40 (,m, 5 H)
Following procedures outlined for Examples 3b) and 4b) the intermediate compounds of the general formula (II) listed in the Table 9. were prepared.
TABLE 9
(II)
Figure US07655663-20100202-C00175
Characterisation (M.p., LC/MS or
Example R1 aromatic protons by 1H-NMR [DMSO-d6])
9.1.
Figure US07655663-20100202-C00176
 		6.55 (dd, 1 H), 6.79 (d, 1 H,), 7.48 (td, 1 H), 8.07 (dd, 1 H)
9.2.
Figure US07655663-20100202-C00177
 		104-106° C.
9.3.
Figure US07655663-20100202-C00178
 		234-236° C. as dihydrochloride
9.4.
Figure US07655663-20100202-C00179
 		2.12 (s, 3 H), 6.72 (d, 1 H), 7.33 (dd, 1 H), 7.92 (d, 1 H)
9.5.
Figure US07655663-20100202-C00180
 		2.26 (s, 3 H), 6.47 (m, 2 H), 8.03 (d, 1 H)
9.6.
Figure US07655663-20100202-C00181
 		238-240° C. as dihydrochloride
9.7.
Figure US07655663-20100202-C00182
 		6.84 (d, 1 H), 7.52 (dd, 1 H), 8.05 (d, 1 H)
9.8.
Figure US07655663-20100202-C00183
 		6.75 (d, 1 H), 7.60 (d, 1 H), 8.12 (s, 1 H)
9.9.
Figure US07655663-20100202-C00184
 		86-89° C.
9.10.
Figure US07655663-20100202-C00185
 		2.37 (s, 3 H), 6.72 (d, 1 H), 7.87 (d, 1 H)
9.11.
Figure US07655663-20100202-C00186
 		117-119° C.
9.12.
Figure US07655663-20100202-C00187
 		135-139° C.
9.13.
Figure US07655663-20100202-C00188
 		6.65 (d, 1 H), 8.27 (d, 1 H)
9.14.
Figure US07655663-20100202-C00189
 		7.78 (s, 1 H), 8.26 (s, 1 H)
9.15.
Figure US07655663-20100202-C00190
 		6.80 (d, 1 H), 8.00 (d, 1 H)
9.16.
Figure US07655663-20100202-C00191
 		296-303° C. as dihydrochloride
9.17.
Figure US07655663-20100202-C00192
 		[MH]+ = 204
9.18.
Figure US07655663-20100202-C00193
 		2.33 (s, 3 H), 6.51 (d, 1 H), 7.96 (d, 1 H)
9.19.
Figure US07655663-20100202-C00194
 		112-114° C.
9.20.
Figure US07655663-20100202-C00195
 		167-170° C.
9.21.
Figure US07655663-20100202-C00196
 		67-68° C.
9.22.
Figure US07655663-20100202-C00197
 		7.60 (m, 2 H), 7.72 (d, 1 H), 8.15 (m, 1 H), 8.32 (1 H, d),
9.23.
Figure US07655663-20100202-C00198
 		260-262° C. as dihydrochloride
9.24.
Figure US07655663-20100202-C00199
 		253-256° C. as dihydrochloride
9.25.
Figure US07655663-20100202-C00200
 		7.34 (m, 1 H), 7.58 (m, 2 H), 7.79 (dd, 1 H), 8.81 (s, 1 H)
9.26.
Figure US07655663-20100202-C00201
 		7.03 (t, 1 H), 7.26 (t, 1 H), 7.42 (d, 1 H), 7.74 (d, 1 H)
9.27.
Figure US07655663-20100202-C00202
 		274-275° C. as dihydrochloride
9.28.
Figure US07655663-20100202-C00203
 		113-115° C.
9.29.
Figure US07655663-20100202-C00204
 		216-223° C. as dihydrochloride
9.30.
Figure US07655663-20100202-C00205
 		3.70 (s, 6 H)

Claims (9)

1. A compound of Formula (I)
Figure US07655663-20100202-C00206
wherein:
R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings which is, in a given case, independently from each other mono-or disubstituted by one or two of the following groups: C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalogenomethyl, methylthio, nitro, cyano, amino or phenyl;
thienyl, furyl or benzyl;
p-toluenesulfonyl;
acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl, phenyl ; phenyl, pyridyl or phenylethenyl substituted with one or more alkyl-and/or alkoxy-or nitro or halogen atom; phenylethenyl or phenylethyl substituted with alkylene-dioxy;
piperidin- 1-yl, 4-methylpiperazin- 1-yl, or pyrrolidin-1-yl;
B stands for a group of formula (4) or (5):
Figure US07655663-20100202-C00207
R2 stands for hydrogen atom or fluorine atom; and
R3 stands for fluorine atom;
and salts thereof.
2. The compound of claim 1 wherein:
R1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalogenomethyl, methylthio, nitro, cyano;
thienyl or furyl;
p-toluenesulfonyl; or
acyl group of formula R1a—CO, wherein R1a means C1-4 alkyl, phenyl; phenyl, pyridyl or phenylethenyl substituted with one or more alkyl- and/or alkoxy- or nitro or halogen atom; phenylethenyl or phenylethyl substituted with alkylene-dioxy;
piperidin- 1-yl, 4-methylpiperazin- 1-yl, or pyrrolidin- 1-yl,
B stands for
a group of formula (4) or (5)
Figure US07655663-20100202-C00208
R2 stands for hydrogen atom or fluorine atom; and
R3 stands for fluorine atom; and salts, thereof.
3. The compound of claim 2 wherein
R1 means 2-pyrimidinyl, 2-pyrazinyl, chloro- and cyano-substituted pyridazinyl, or cyano-substituted 2-pyridinyl;
B stands for a group of formula (4) or (5)
Figure US07655663-20100202-C00209
and
R2 and R3 stand for fluorine atom.
4. The compound of claim 1 which is (2S)-4,4-difluoro-1-(2-{[8-(2-pyrimidinyl)-8-azabicyclo[3.2.1 ]oct-3-yl]exo-amino }acetyl)-2-pyrrolidine carbonitrile.
5. The compound of claim 1 which is (2S,4S)-4-fluoro-1-(2-{[8-(2-pyrazinyl)-8-azabicyclo- [3.2.1 ]-oct-3-yl]exo-amino }acetyl)-2-pyrrolidinecarbonitrile.
6. A pharmaceutical formulation comprising a compound of claim 1 or salts thereof.
7. A process for the preparation of the compounds of claim 1 wherein the meanings of R1, B, R2 and R3 are the same as defined in claim 1—characterised in that, a compound of the general formula (II)
Figure US07655663-20100202-C00210
wherein the meanings of R1 and B are as defined above—is reacted with a compound of the general formula (III)
Figure US07655663-20100202-C00211
wherein the meanings of R2 and R3 are as defined above—and the resulting compound is of the general formula (I)
Figure US07655663-20100202-C00212
or its salt is isolated from the reaction mixture.
8. The compound according to claim 1, wherein R1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, tetrazolyl or triazinyl.
9. The compound according to claim 2, wherein R1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl.
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Families Citing this family (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1399433B1 (en) * 2001-06-27 2007-08-22 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
HUP0202001A2 (en) * 2002-06-14 2005-08-29 Sanofi-Aventis Azabicyclo-octane and nonane derivatives with ddp-iv inhibiting activity
TW200401635A (en) * 2002-07-23 2004-02-01 Yamanouchi Pharma Co Ltd 2-Cyano-4-fluoropyrrolidine derivative or salt thereof
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
JP4806628B2 (en) 2003-05-05 2011-11-02 プロビオドルグ エージー Glutaminyl cyclase inhibitor
HU227684B1 (en) 2003-08-29 2011-11-28 Sanofi Aventis Adamantane and azabicyclo-octane and nonane derivatives and their use as dpp-iv inhibitors
EP2338490A3 (en) 2003-11-03 2012-06-06 Probiodrug AG Combinations useful for the treatment of neuronal disorders
KR20170005163A (en) 2003-11-17 2017-01-11 노파르티스 아게 Use of dipeptidyl peptidase iv inhibitors
EP2165703A3 (en) 2004-01-20 2012-03-28 Novartis Pharma AG Direct compression formulation and process
AU2005210285B2 (en) 2004-02-05 2008-01-24 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
BRPI0507485A (en) 2004-02-05 2007-07-10 Probiodrug Ag new glutaminyl cyclase inhibitors
FR2870538B1 (en) * 2004-05-19 2006-07-14 Servier Lab NOVEL DERIVATIVES OF PYRROLIDINES AND THIAZOLIDINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
MX2007004305A (en) 2004-10-12 2007-06-18 Glenmark Pharmaceuticals Sa Novel dipeptidyl peptidase iv inhibitors, pharmaceutical compositions containing them, and process for their preparation.
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
DOP2006000008A (en) * 2005-01-10 2006-08-31 Arena Pharm Inc COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED AFFECTIONS AND FOR THE TREATMENT OF AFFECTIONS THAT IMPROVE THROUGH AN INCREASE IN THE BLOOD CONCENTRATION OF GLP-1
JP2008024592A (en) * 2005-01-28 2008-02-07 Taisho Pharmaceut Co Ltd Cyanopyrrolidine derivative-containing composition for solid preparation, solid preparation containing the composition and process for producing the solid preparation
AU2006239929B2 (en) 2005-04-22 2011-11-03 Alantos Pharmaceuticals Holding, Inc. Dipeptidyl peptidase-IV inhibitors
CN101232873A (en) * 2005-08-11 2008-07-30 霍夫曼-拉罗奇有限公司 Pharmaceutical composition comprising a dpp-iv inhibitor
DK1942898T4 (en) 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for the treatment of diabetes
KR101368988B1 (en) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 Dipeptidyl peptidase inhibitors
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
US20090156465A1 (en) 2005-12-30 2009-06-18 Sattigeri Jitendra A Derivatives of beta-amino acid as dipeptidyl peptidase-iv inhibitors
JP5101489B2 (en) 2006-03-08 2012-12-19 杏林製薬株式会社 Process for producing aminoacetylpyrrolidinecarbonitrile derivative and its production intermediate
CN101050194B (en) * 2006-04-05 2013-08-21 上海恒瑞医药有限公司 Derivative of bicyclo-octanes class, preparation method, and application of medicine
EP2369341A3 (en) * 2006-04-11 2012-01-04 Arena Pharmaceuticals, Inc. Methods of using gpr119 receptor to identify compounds useful for increasing bone mass in an individual
PE20071221A1 (en) 2006-04-11 2007-12-14 Arena Pharm Inc GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (en) 2006-05-04 2008-04-25 Boehringer Ingelheim Int USES OF DPP IV INHIBITORS
NO347644B1 (en) 2006-05-04 2024-02-12 Boehringer Ingelheim Int Polymorphs
EP2061767B1 (en) 2006-08-08 2014-12-17 Sanofi Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
ATE554085T1 (en) 2006-11-30 2012-05-15 Probiodrug Ag NEW INHIBITORS OF GLUTAMINYL CYCLASE
CN101230058A (en) 2007-01-23 2008-07-30 上海恒瑞医药有限公司 Bicycle aza alkyl derivative, preparation method and use in medicine thereof
CN101230059B (en) * 2007-01-23 2011-08-17 上海恒瑞医药有限公司 Bicycle aza alkyl derivative, preparation method and use in medicine thereof
DE102007005045B4 (en) 2007-01-26 2008-12-18 Sanofi-Aventis Phenothiazine derivatives, process for their preparation and their use as medicines
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
JPWO2008114857A1 (en) 2007-03-22 2010-07-08 杏林製薬株式会社 Process for producing aminoacetylpyrrolidinecarbonitrile derivative
JP5667440B2 (en) 2007-04-18 2015-02-12 プロビオドルグ エージー Thiourea derivatives as glutaminyl cyclase inhibitors
JP5603770B2 (en) 2007-05-31 2014-10-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング CCR2 receptor antagonist and use thereof
GB0713602D0 (en) * 2007-07-12 2007-08-22 Syngenta Participations Ag Chemical compounds
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
US8338450B2 (en) * 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
RU2487866C2 (en) * 2008-01-23 2013-07-20 Цзянсу Хэнсох Фармасьютикал Ко., Лтд. Dicycloazaalkane derivatives, methods for production thereof and use thereof in medicine
AR071175A1 (en) 2008-04-03 2010-06-02 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO
EP2146210A1 (en) * 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
KR20200118243A (en) 2008-08-06 2020-10-14 베링거 인겔하임 인터내셔날 게엠베하 Treatment for diabetes in patients inappropriate for metformin therapy
WO2010016584A1 (en) * 2008-08-07 2010-02-11 杏林製薬株式会社 Process for production of bicyclo[2.2.2]octylamine derivative
CN102186474A (en) * 2008-08-14 2011-09-14 杏林制药株式会社 stable pharmaceutical composition
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
WO2010054183A2 (en) * 2008-11-07 2010-05-14 President And Fellows Of Harvard College Dyes, compositions and related methods of use
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
EA020548B1 (en) 2008-12-19 2014-12-30 Бёрингер Ингельхайм Интернациональ Гмбх Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd
GB2483614B (en) 2009-06-18 2014-12-03 Lupin Ltd 2-Amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent dpp-iv inhibitors
AR077642A1 (en) 2009-07-09 2011-09-14 Arena Pharm Inc METABOLISM MODULATORS AND THE TREATMENT OF DISORDERS RELATED TO THE SAME
CN102482312A (en) 2009-08-26 2012-05-30 赛诺菲 Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
SG178953A1 (en) 2009-09-11 2012-04-27 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
AU2010323068B2 (en) 2009-11-27 2015-09-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
MX2012006964A (en) 2009-12-17 2012-07-17 Boehringer Ingelheim Int New ccr2 receptor antagonists and uses thereof.
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
AU2011226074B2 (en) 2010-03-10 2015-01-22 Vivoryon Therapeutics N.V. Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
CN102918027A (en) 2010-04-06 2013-02-06 艾尼纳制药公司 Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8541596B2 (en) 2010-04-21 2013-09-24 Probiodrug Ag Inhibitors
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
WO2011141477A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
JP2013526507A (en) 2010-05-12 2013-06-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング NOVEL CCR2 RECEPTOR ANTAGONIST, PROCESS FOR PRODUCING THE SAME AND USE THEREOF AS DRUG
US8841313B2 (en) 2010-05-17 2014-09-23 Boehringer Ingelheim International Gmbh CCR2 antagonists and uses thereof
EP2576542B1 (en) 2010-05-25 2015-04-22 Boehringer Ingelheim International GmbH Cyclic amide derivatives of pyridazine-3-carboxylic acids and their use in the treatment of pulmonary, pain, immune related and cardiovascular diseases
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
US8933024B2 (en) 2010-06-18 2015-01-13 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
BR112013008100A2 (en) 2010-09-22 2016-08-09 Arena Pharm Inc "gpr19 receptor modulators and the treatment of disorders related thereto."
AR083878A1 (en) 2010-11-15 2013-03-27 Boehringer Ingelheim Int VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683702B1 (en) 2011-03-08 2014-12-24 Sanofi New substituted phenyl oxathiazine derivatives, method for their manufacture, medicines containing these compounds and their application
EP2683698B1 (en) 2011-03-08 2017-10-04 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
US8901114B2 (en) 2011-03-08 2014-12-02 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
EP2683703B1 (en) 2011-03-08 2015-05-27 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
ES2570167T3 (en) 2011-03-16 2016-05-17 Probiodrug Ag Benzimidazole derivatives as glutaminyl cyclase inhibitors
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20140066369A1 (en) 2011-04-19 2014-03-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140051714A1 (en) 2011-04-22 2014-02-20 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140038889A1 (en) 2011-04-22 2014-02-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
JP5786258B2 (en) 2011-07-15 2015-09-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel and selective CCR2 antagonist
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2567959B1 (en) 2011-09-12 2014-04-16 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2760862B1 (en) 2011-09-27 2015-10-21 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
CN104583194A (en) * 2012-05-11 2015-04-29 艾伯维公司 Pyridazine and pyridine derivatives as NAMPT inhibitors
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
CN103508931B (en) * 2012-06-25 2016-03-02 广东东阳光药业有限公司 Six hydrogen pentalene derivatives, its preparation method and in application pharmaceutically
TWI500613B (en) 2012-10-17 2015-09-21 Cadila Healthcare Ltd Novel heterocyclic compounds
EP2911655A1 (en) 2012-10-24 2015-09-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Tpl2 kinase inhibitors for preventing or treating diabetes and for promoting -cell survival
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US9840489B2 (en) 2013-12-20 2017-12-12 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Piperidine carboxamide compound, preparation method, and usage thereof
WO2015128453A1 (en) 2014-02-28 2015-09-03 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor
CN104529856A (en) * 2015-01-13 2015-04-22 佛山市赛维斯医药科技有限公司 Nitro adamantine amide derivative and preparing method and application thereof
CN104529858A (en) * 2015-01-13 2015-04-22 佛山市赛维斯医药科技有限公司 Derivative with halogeneated and amides and preparation method and application thereof
EP3053577A1 (en) * 2015-02-09 2016-08-10 F. Hoffmann-La Roche AG Compounds for the treatment of cancer
WO2016128343A1 (en) 2015-02-09 2016-08-18 F. Hoffmann-La Roche Ag Compounds for the treatment of cancer
PT3265126T (en) 2015-03-03 2021-08-30 Saniona As Tesofensine, beta blocker combination formulation
AU2016229982B2 (en) 2015-03-09 2020-06-18 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10426818B2 (en) 2015-03-24 2019-10-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Method and pharmaceutical composition for use in the treatment of diabetes
JP6917910B2 (en) 2015-07-02 2021-08-11 セントレクシオン セラピューティクス コーポレイション (4-((3R, 4R) -3-methoxytetrahydro-pyran-4-ylamino) piperidine-1-yl) (5-methyl-6-(((2R, 6S) -6- (P-tolyl) tetrahydro) -2H-pyran-2-yl) methylamino) pyrimidine-4yl) metanone citrate
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
EP3606527A1 (en) 2017-04-03 2020-02-12 Coherus Biosciences, Inc. Ppar-gamma agonist for treatment of progressive supranuclear palsy
ES2812698T3 (en) 2017-09-29 2021-03-18 Probiodrug Ag Glutaminyl cyclase inhibitors
AU2018386298B2 (en) 2017-12-15 2023-09-07 Praxis Biotech LLC Inhibitors of fibroblast activation protein

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009544A1 (en) 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. 2-cyano-4-fluoropyrrolidine derivative or its salt
US20040024236A1 (en) 2002-06-20 2004-02-05 Vanduffel Koen Antoon Kornelis (Stabilised) peroxide compositions phlegmatised with a specific unsaturated phlegmatising agent
US20040242636A1 (en) * 2001-06-27 2004-12-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2005A (en) * 1841-03-16 Improvement in the manner of constructing molds for casting butt-hinges
US2004A (en) * 1841-03-12 Improvement in the manner of constructing and propelling steam-vessels
US3225037A (en) * 1959-03-30 1965-12-21 Sterling Drug Inc 10-[(amino- and acylamino-1-piperidyl) lower-alkyl]-phenothiazines
GB1460389A (en) * 1974-07-25 1977-01-06 Pfizer Ltd 4-substituted quinazoline cardiac stimulants
US4302455A (en) * 1980-04-14 1981-11-24 Merck & Co., Inc. 2-(4-Aminopiperidino)pyrazines
US5001125A (en) * 1984-03-26 1991-03-19 Janssen Pharmaceutica N.V. Anti-virally active pyridazinamines
JP2869561B2 (en) * 1989-05-22 1999-03-10 大塚製薬株式会社 Platelet adhesion inhibitor
CA2106840A1 (en) * 1992-09-25 1994-03-26 Marco Baroni Heteroarylazetidines and -pyrrolidines, process for their preparation and pharmaceutical compositions containing them
ES2079323B1 (en) * 1994-06-21 1996-10-16 Vita Invest Sa DERIVATIVES OF INDOL USEFUL FOR THE TREATMENT OF THE MIGRAINE, COMPOSITION AND CORRESPONDING USE.
UA51716C2 (en) * 1996-07-08 2002-12-16 Авентіс Фармасьютікалз Продактс Інк. combinations possessing hypotensive, cardioprotective, anti-ishemic, and antilipolytic agents, a pharmaceutical composition and METHOD OF TREATMENT
TW492957B (en) * 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
FR2780057B1 (en) * 1998-06-18 2002-09-13 Sanofi Sa PHENOXYPROPANOLAMINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP1428824A1 (en) * 1999-05-21 2004-06-16 Abbott Laboratories Heterocyclic substituted aminoazacycles useful as central nervous system agents
TW583185B (en) * 2000-06-13 2004-04-11 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines and pharmaceutical composition for inhibiting dipeptidyl peptidase-IV (DPP-IV) or for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV comprising the same
ATE450504T1 (en) 2000-08-10 2009-12-15 Mitsubishi Tanabe Pharma Corp PROLINE DERIVATIVES AND THEIR USE AS MEDICATIONS
US7138397B2 (en) * 2000-10-06 2006-11-21 Tanabe Seiyaku Co., Ltd. Nitrogenous 5-membered ring compounds
TWI243162B (en) * 2000-11-10 2005-11-11 Taisho Pharmaceutical Co Ltd Cyanopyrrolidine derivatives
JP2002264450A (en) * 2000-12-21 2002-09-18 Ricoh Co Ltd Image processing unit, imaging apparatus, imaging method and image processing system
CA2433090A1 (en) 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
GB0115517D0 (en) * 2001-06-25 2001-08-15 Ferring Bv Novel antidiabetic agents
KR20040015298A (en) * 2001-06-27 2004-02-18 스미스클라인 비참 코포레이션 Fluoropyrrolidines as dipeptidyl peptidase inhibitors
CN1706726A (en) * 2004-02-17 2005-12-14 梅加特雷德国际公司 Container with luminescent features

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242636A1 (en) * 2001-06-27 2004-12-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US20040024236A1 (en) 2002-06-20 2004-02-05 Vanduffel Koen Antoon Kornelis (Stabilised) peroxide compositions phlegmatised with a specific unsaturated phlegmatising agent
WO2004009544A1 (en) 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. 2-cyano-4-fluoropyrrolidine derivative or its salt
US20050176771A1 (en) 2002-07-23 2005-08-11 Masahiko Hayakawa 2-Cyano-4-fluoropyrrolidine derivative or its salt

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Isomer." Retrieved online via the Internet [Dec. 9, 2008] URL: www.en.wikipedia.org/wiki/isomer. *
"Tautomer." Retrieved online via the Internet [Dec. 9, 2008] URL:www.en.wikipedia.org/wiki/Tautomer. *
Morissette et al. Advanced Drug Delivery Reviews 2004, 56, 275-300. *
Patani, George A. Bioisosterism: A rational approach in drug design. Chem. Rev. 96 (1996) 3147-3176. *
Vippagunta et al., abstract, Vippagunta, Sudha R. "Crystalline Solids." Advanced Drug Delivery Reviews 48(2001): 3-26. *

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